Oral Semaglutide for the MACE Indication Is Expected to Be Completed in the Sally Hughes and Joshua J

CLINICAL PHARMACOLOGY UPDATE

According to a manufacturer press release, the FDA review Oral Semaglutide for the MACE indication is expected to be completed in the Sally Hughes and Joshua J. Neumiller ﬁrst quarter of 2020 (3).

Mechanism of Action Introduction GLP-1 receptor agonists work to lower glycemia via Oral semaglutide (Rybelsus) is the first oral glucagon-like several mechanisms, including stimulation of glucose- peptide 1 (GLP-1) receptor agonist product approved by dependent insulin secretion from pancreatic b-cells, the U.S. Food and Drug Administration (FDA) for the suppression of glucagon secretion from pancreatic a- treatment of type 2 diabetes (1). As a class, GLP-1 receptor cells, and delaying of gastric emptying (4). The novelty agonists are widely used and recommended for the of oral semaglutide is in the formulation that allows for management of type 2 diabetes. The American Diabetes oral administration and absorption of the drug. Oral Association’s Standards of Medical Care in Diabetes—2019 semaglutide is coformulated with the absorption en- recommend GLP-1 receptor agonists with proven car- hancer sodium N-(8-[2-hydroxylbenzoyl] amino) cap- diovascular benefit as one of the two preferred options for rylate (SNAC) (5). Coformulation with SNAC helps add-on therapy in patients with type 2 diabetes and facilitate semaglutide absorption in the stomach by established atherosclerotic cardiovascular disease after increasing the local pH, which leads in turn to increased metformin and lifestyle intervention (2). Drugs in this drug solubility and protection against proteolytic class are likewise generally recommended as add-on degradation (6). therapy after metformin in patients not meeting in- dividualized glycemic goals when there is a compelling need to minimize hypoglycemia or promote weight loss Potential Advantages (2). Despite their clinical benefits, GLP-1 receptor agonists The primary advantage of this semaglutide formulation is historically have required self-administration by sub- its oral administer route, which makes it an option for cutaneous injection. The availability of oral semaglutide patients who are unwilling or unable to self-inject glucose- provides a new option within the class for patients lowering medications. Oral administration does not ap- who are unable or unwilling to self-administer an pear to diminish the glucose- or weight-lowering efficacy injectable agent. of the agent, as demonstrated in the PIONEER 4 study (7). PIONEER 4 compared the addition of oral semaglutide or subcutaneous liraglutide to background metformin with Indication or without a sodium–glucose cotransporter 2 (SGLT2) inhibitor in patients with type 2 diabetes and a baseline Oral semaglutide received FDA approval in September A1C of 7.0–9.5%. After 26 weeks of treatment, oral 2019 for use as adjunct to diet and exercise to improve semaglutide (target dose of 14 mg once daily) resulted in a glycemic control in adults with type 2 diabetes (1). The mean A1C reduction from baseline of 1.2% compared with product is available in 3-, 7-, and 14-mg tablets. The a reduction of 1.1% observed with liraglutide (target dose manufacturer recommends initiating oral semaglutide at of 1.8 mg once daily), thus demonstrating noninferiority. the 3-mg dose once daily and then increasing the dose to In terms of weight loss, mean weight reductions from 7 mg once daily dose after 30 days. For patients requiring baseline of 4.4 and 3.1 kg were seen in the oral sem- additional glycemic lowering, the dose can be further aglutide and liraglutide groups, respectively (P 5 increased to 14 mg once daily after at least 30 days at the 0.0003) (7). 7-mg dose (1). The manufacturer has filed an application with the FDA for a second indication to reduce major Oral semaglutide has likewise compared favorably when adverse cardiovascular events (MACE) in adults with type studied against the SGLT2 inhibitor empagliflozin (8). 2 diabetes and established cardiovascular disease (3). The PIONEER 2 trial enrolled patients with type 2

College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA Corresponding author: Joshua J. Neumiller, [email protected] https://doi.org/10.2337/cd19-0079 ©2019 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for proﬁt, and the work is not altered. See http://www.diabetesjournals.org/content/license for details.

1 Clinical Diabetes Online Ahead of Print, published online December 5, 2019 CLINICAL PHARMACOLOGY UPDATE Oral Semaglutide diabetes uncontrolled on metformin (baseline A1C Commentary 7.0–10.5%). Participants were randomized to receive Oral semaglutide, while not the first agent in its class, is either oral semaglutide 14 mg once daily or empagli- the first orally administered GLP-1 receptor agonist on the flozin 25 mg once daily. At 26 weeks, oral semaglutide market. In our opinion, this is a welcome addition and treatment resulted in a superior reduction in mean A1C provides an additional option for patients and providers. from baseline when compared with empagliflozin (–1.3 However, although oral administration may be an ad- vs. –0.9%, P , 0.0001). Oral semaglutide additionally vantage for some patients, the need to take the medication demonstrated better weight loss at week 52 when on an empty stomach may prove a barrier for others. compared with empagliflozin treatment (–4.7 vs. –3.8 kg, P 5 0.0114) (8). Bottom Line fi Potential Disadvantages Oral semaglutide, the rst oral GLP-1 receptor agonist on the market, has compared favorably in clinical trials As with all agents in the GLP-1 receptor agonist class, oral against other glucose-lowering agents in adults with type semaglutide is associated with gastrointestinal adverse 2 diabetes. Time will tell if this agent will also receive a reactions such as nausea, abdominal pain, and vomiting cardiovascular indication and how it will be incorporated (1). Although oral administration is a potential advantage into routine clinical practice. with this product, current recommendations for administration may prove difficult for some patients. It is DUALITY OF INTEREST recommended that oral semaglutide be administered at fl least 30 min before the first food, beverage, or other oral No potential con icts of interest relevant to this article were reported. medications of the day and that it be taken with no more than 4 oz plain water only (1). The prescribing in- AUTHOR CONTRIBUTIONS formation warns that not following these directions will lessen the effect of the medication. These instructions may Both authors contributed to and were involved in the research, writing, and editing of this article. J.J.N. is the guarantor of this prove difficult for some patients, particularly if they are work and, as such, had full access to all of the references cited taking other oral medications that are recommended to be and takes responsibility for the accuracy of the content. taken first thing in the morning on an empty stomach, such as levothyroxine or bisphosphonates. Furthermore, the REFERENCES prescribing information notes that, when coadministered 1. Novo Nordisk. Rybelsus (semaglutide) tablets [prescribing with thyroxine, the total exposure (area under the curve) information]. Plainsboro, NJ, Novo Nordisk, 2019 of thyroxine was increased by 33% (1), indicating that 2. American Diabetes Association. 9. Pharmacologic ap- coadministration could result in excessive thyroxine proaches to glycemic treatment: Standards of Medical Care in levels. Accordingly, the manufacturer suggests that in- Diabetes—2019. Diabetes Care 2019;42(Suppl 1):S90–S102 creased clinical or laboratory monitoring be considered fi for medications with a narrow therapeutic index when 3. Novo Nordisk. Rybelsus (semaglutide tablets), the rst GLP-1 in a tablet approved in the US. Available from www.novonordisk. taken concomitantly with oral semaglutide. com/bin/getPDF.2172050.pdf. Accessed 9 October 2019 4. Neumiller JJ. Incretin-based therapies. Med Clin North Am – Cost 2015;99:107 129 5. Buckley ST, Bækdal TA, Vegge A, et al. Transcellular At the time of this writing, the published average stomach absorption of a derivatized glucagon-like peptide-1 wholesale price (AWP) for oral semaglutide was $30.89 receptor agonist. Sci Transl Med 2018;10:eaar7047 per tablet (all doses), equating to a monthly cost of 6. Davies M, Pieber TR, Hartoft-Nielsen ML, Hansen OKH, $926.92 (9). It should be noted that the listed AWP does Jabbour S, Rosenstock J. Effect of oral semaglutide compared not account for discounts, rebates, or other price ad- with placebo and subcutaneous semaglutide on glycemic justments often involved in prescription sales that affect control in patients with type 2 diabetes: a randomized clinical the actual cost incurred by patients (2). As a basis for trial. JAMA 2017;318:1460–1470 comparison, the published monthly AWP price for oral 7. Pratley R, Amod A, Hoff ST, et al; PIONEER 4 investigators. semaglutide is the same as the published monthly AWP Oral semaglutide versus subcutaneous liraglutide and placebo price for the once-weekly injectable semaglutide for- in type 2 diabetes (PIONEER 4): a randomised, double-blind, mulation (Ozempic) (9). phase 3a trial. Lancet 2019;394:39–50

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8. Rodbard HW, Rosenstock J, Canani LH, et al; PIONEER 2 9. Truven Health Analytics. Introduction to RED BOOK Investigators. Oral semaglutide versus empagliﬂozin in Online, 2019. Available from www.micromedexsolutions. patients with type 2 diabetes uncontrolled on metformin: com/micromedex2/4.34.0/WebHelp/RED_BOOK/ the PIONEER 2 trial. Diabetes Care 2019;17:dc190883. Epub Introduction_to_REDB_BOOK_Online.htm. Accessed 9 October ahead of print (DOI: 10.2337/dc19-0883) 2019

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